美国麻省理工学院和哈佛大学布罗德研究所Beth Stevens和Evan Z. Macosko团队合作取得一项新成果。经过不懈努力，他们发现将iPSC衍生的人小胶质细胞置于脑底物中，能够在体外产生和调控不同的转录状态。2023年7月27日出版的《自然—免疫学》发表了这项成果。

研究人员在体外建立了一个模拟人类小胶质细胞转录状态的平台。研究发现，将人类干细胞分化的小胶质细胞与突触体、髓鞘碎片、凋亡神经元或合成淀粉样蛋白-β原纤维接触会产生转录多样性，这些转录多样性可映射到人脑小胶质细胞中鉴定的基因特征，这些特征与一种富含神经退行性疾病的状态匹配，其包括与疾病相关的小胶质细胞。

使用新的慢病毒转染方法，研究人员证明转录因子MITF驱动与疾病相关的转录特征和高度吞噬状态。总之，研究人员开发的这种工具能够在稳态和疾病相关环境中对人类小胶质细胞状态进行操作和功能鉴定。

据了解，小胶质细胞是脑实质的巨噬细胞，主要参与调控阿尔茨海默病等神经退行性疾病。这些细胞具有不同转录亚型-状态。由于缺乏模拟和操纵这些细胞的工具，对状态功能的了解甚少，特别是其在人类小胶质细胞中的功能。

附：英文原文

Title: Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Author: Dolan, Michael-John, Therrien, Martine, Jereb, Saa, Kamath, Tushar, Gazestani, Vahid, Atkeson, Trevor, Marsh, Samuel E., Goeva, Aleksandrina, Lojek, Neal M., Murphy, Sarah, White, Cassandra M., Joung, Julia, Liu, Bingxu, Limone, Francesco, Eggan, Kevin, Hacohen, Nir, Bernstein, Bradley E., Glass, Christopher K., Leinonen, Ville, Blurton-Jones, Mathew, Zhang, Feng, Epstein, Charles B., Macosko, Evan Z., Stevens, Beth

Issue&Volume: 2023-07-27

Abstract: Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

DOI: 10.1038/s41590-023-01558-2

Source: https://www.nature.com/articles/s41590-023-01558-2